The ubiquitin-proteasome system is a signaling mechanism that decomposes proteins to maintain cellular homeostasis and controls cell survival. Ubiquitin is a protein in vivo that conjugates and thus marks a condemned protein for degradation, and a proteasome is an enzyme that actually decomposes a protein.
When ubiquitin tags the condemned protein as a label, a proteasome recognizes the label and decomposes the protein. Then, ubiquitin is cleaved off the protein and repeats the same role. However, the protein decomposed by the ubiquitin-proteasome system is degraded into small peptides or amino acids and are recycled in synthesis of another protein.
The ubiquitin-proteasome system is also involved in a cell division process and an immune system that decomposes and disrupts an external antigen, and damages on the proteasome system are deemed as pathogenesis of neurodegenerative diseases such as Huntington diseases that occur when undegraded proteins accumulate in neurons. In this regard, since the proteasome system plays a vital role in a protein decomposition process, enlightenment on the structure or role of the system increases attention in the development of treating agents for various diseases.
In terms of cancer, the ubiquitin-proteasome system decomposes intercellular proteins such as Bax or Noxa that induce apoptosis and thus, the cancer cells may continue its proliferation. Thus, a drug that inhibits a proteasome is expected to promote apoptosis of cancer cells, and, in practice, bortezomib, for the first, and carfilzomib, for the second, have been approved by FDA as proteasome inhibitors.
Bortezomib (N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid; available as Velcade™ from Millennuim Pharmaceuticals) is 26S proteasome inhibitor that is approved to be used in the treatment of various neoplastic diseases, particularly, in the treatment of relapsed multiple myeloma and mantle cell lymphoma.
The bortezomib has been reported that a boron atom in the bortezomib binds to a catalyst site, and this suppresses proteasome activities and decreases decomposition of a pro-apoptotic factor, which results in promotion of apoptosis of cells.
Korean Patent Publication No. 2007-7027765 discloses a method and a composition using a proteasome inhibitor for treatment and management of cancer and other diseases, and the same publication also discloses bortezomib exhibiting an anticancer effect on multiple myeloma and lymphoma, whereas an anticancer effect of the bortezomib on leukemia or solid cancers has not been testified.